The present invention relates to a method of manufacturing substance GM-95, which has an anti-cancer activity, and also relates to intermediates in the manufacture of substance GM-95.
Regarding substance GM-95, which has an anti-cancer activity, International Publication No. WO00/24747 discloses isolation from a culture. The structure of substance GM-95 is unique; it is a macrocyclic compound comprising seven oxazole rings and a thiazoline ring connected together. No chemical manufacturing method has been known for these macrocyclic compounds comprising sequential 5-membered hetero-cyclic rings, such as substance GM-95 so far.
It is an object of the present invention to provide a method of manufacturing substance GM-95, and intermediates in the manufacture of substance GM-95.
That is, the present invention relates to a method of manufacturing substance GM-95 having general formula [I]
characterized by (a) deprotecting a macrocyclic compound having general formula [II]
(wherein, R1""s are the same or different and each represents a lower alkyl group, and R2 represents a thiol protecting group) by removing acetal protecting groups (the R1""s) thereof, and forming an oxazole ring through an intramolecular cyclization reaction between the thus produced formyl group and an amide group, and (b) deprotecting the resulting macrocyclic compound represented by general formula [III]
(wherein, R2 is as mentioned above) by removing the thiol protecting group (R2) thereof, and forming a thiazoline ring through an intramolecular cyclization reaction between a thiol group thus produced and an amide group. Moreover, the present invention relates to the macrocyclic compounds represented by above-mentioned general formulae [II] and [III], which are useful as intermediates in the manufacture of substance GM-95.
Specifically, the present specification provides the following inventions.
Item 1: A method of manufacturing substance GM-95 having general formula [I], characterized by deprotecting the thiol protecting group (R2) of the macrocyclic compound having general formula [III] and forming a thiazoline ring through an intramolecular cyclization reaction between a thiol group thus produced and an amide group.
Item 2: A method of manufacturing substance GM-95 having general formula [I], characterized by (a) deprotecting acetal protecting groups (the R1""s) of the macrocyclic compound having general formula [II] and forming an oxazole ring through an intramolecular cyclization reaction between a formyl group thus produced and an amide group, and
(b) deprotecting the thiol protecting group (R2) of the resulting macrocyclic compound having general formula [III] and forming a thiazoline ring through an intramolecular cyclization reaction between a thiol group thus produced and an amide group.
Item 3: The macrocyclic compound having general formula [II].
Item 4: The macrocyclic compound having general formula [III].
Item 5: A method of manufacturing the macrocyclic compound having general formula [II], characterized by (a) carrying out dehydration condensation between an acetal derivative having general formula [IV-a]
(wherein, the R1""s are as mentioned above, and R3 represents a carboxyl protecting group) and a thiol derivative having general formula [V-a]
(wherein, R2 is as mentioned above, and R4 represents an amino protecting group), and
(b) deprotecting the amino protecting group (R4) and the carboxyl protecting group (R3) of the resulting amide derivative having general formula [VI]
(wherein, the R1""s, R2, R3 and R4 are as mentioned above) and then carrying out intramolecular cyclization.
Item 6: A method of manufacturing the macrocyclic compound having general formula [II], characterized by (a) carrying out dehydration condensation between an acetal derivative having general formula [IV-b]
(wherein, the R1""s are as mentioned above, and R5 represents an amino protecting group) and a thiol derivative having general formula [V-b]
(wherein, R2 is as mentioned above, and R6 represents a carboxyl protecting group), and
(b) deprotecting the amino protecting group (R5) and the carboxyl protecting group (R6) of the resulting amide derivative having general formula [VII]
(wherein, the R1""s, R2, R5 and R6 are as mentioned above) and then carrying out intramolecular cyclization.
The scheme of the method of manufacturing GM-95 according to the present invention is shown below. 
In the present invention, examples of the lower alkyl groups represented by the R1""s are straight-chain or branched lower alkyl groups having 1 to 6 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, and an s-butyl group, with a methyl group or an ethyl group being preferable, and a methyl group being more preferable.
Examples of the thiol protecting group represented by R2 are protecting groups mentioned in xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 (published 1981) by Greene, for example unsubstituted or substituted benzyl groups such as a benzyl group, a p-methoxybenzyl group, a 4-methylbenzyl group, a 3,4-dimethylbenzyl group, a p-hydroxybenzyl group, a p-acetoxybenzyl group and a p-nitrobenzyl group, a diphenylmethyl group, a trityl group, a t-butyl group, an acetyl group, a benzoyl group, and so on, with an unsubstituted or substituted benzyl group such as a benzyl group, a p-methoxybenzyl group, a 4-methylbenzyl group, a 3,4-dimethylbenzyl group, a p-hydroxybenzyl group, a p-acetoxybenzyl group or a p-nitrobenzyl group, or a diphenylmethyl group, a trityl group, or a t-butyl group being preferable, and a benzyl group, a trityl group, or a t-butyl group being more preferable.
In the present invention, examples of the carboxyl protecting group represented by R3 or R6 are protecting groups mentioned in the above-mentioned xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by Greene, for example straight-chain or branched lower alkyl groups having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an n-butyl group, an isobutyl group, an s-butyl group and a t-butyl group, and an allyl group, a benzyl group, a diphenylmethyl group, and so on, with a methyl group or an ethyl group being preferable for either R3 or R6.
Examples of the amino protecting group represented by R4 or R5 are again protecting groups mentioned in the above-mentioned xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by Greene, for example a methoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a cyclopropylmethoxycarbonyl group, a diisopropylmethoxycarbonyl group, a 2-furanylmethoxycarbonyl group, an isobutoxycarbonyl group, a t-butoxycarbonyl group, a benzyloxycarbonyl group, a formyl group, and so on, with a t-butoxycarbonyl group or a benzyloxycarbonyl group being preferable for either R4 or R5.
Steps of Manufacturing Compound [I] (Substance GM-95) from Compound [II]
(a) Manufacture of Compound [III] from Compound [II]
The present step is a step of deprotecting the macrocyclic compound having general formula [II] by removing the acetal protecting groups (the R1""s) thereof, and forming an oxazole ring through an intramolecular cyclization reaction between the produced formyl group and an amide group.
i) In the above reaction, removing the acetal protecting groups (the R1""s) is carried out in the presence of an acid in a suitable solvent. The solvent may be any solvent so long as it is inert to the reaction; examples are tetrahydrofuran, dioxane, ethyl acetate, and so on. Such solvents may be used alone, or a mixture thereof may be used. Examples of the acid are organic acids such as trifluoroacetic acid and formic acid, and mineral acids such as hydrogen chloride and sulfuric acid. Moreover, the acid can also be used itself. The amount used of the acid is 100 to 2000 mol, preferably 500 to 1000 mol, per mol of the compound having general formula [II]. The reaction temperature is room temperature to about 100xc2x0 C., preferably about 40xc2x0 C. to 80xc2x0 C. The reaction time is about 1 to 48 hours, preferably about 10 to 30 hours.
ii) Next, to form an oxazole ring through an intramolecular cyclization reaction between an amide group and the formyl group produced through the deprotection described above, it is necessary to carry out a dehydration reaction between the formyl group and the amide group in a suitable solvent. The solvent used may be any solvent so long as it is inert to the reaction; examples are chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, dimethylformamide, and soon. Such solvents may be used alone, or a mixture thereof may be used. An example of the dehydrating agent used in the dehydration reaction is a combination of trivalent phosphorous, a halogen and an organic tertiary amine, with a combination of triphenylphosphine, iodine and triethylamine being preferable. Regarding the proportions thereof, 1 to 5 mol of the trivalent phosphorous, 1 to 5 mol of the halogen, and 2 to 10 mol of the organic tertiary amine are used per mol of the compound obtained from deprotecting the compound of general formula [II] by removing the acetal protecting groups. In the specific example, 1 to 5 mol of triphenylphosphine, 1 to 5 mol of iodine, and 2 to 10 mol of triethylamine are used per mol of the compound obtained by deprotecting the compound of general formula [II] by removing the acetal protecting groups.
Regarding the order of addition, it is preferable to add the compound obtained by deprotecting the compound of general formula [II] by removing the acetal protecting groups and then the organic tertiary amine to a mixture of the trivalent phosphorous and the halogen. The reaction temperature is about 0 to 100xc2x0 C., preferably about 20xc2x0 C. to 50xc2x0 C. The reaction time is about 1 to 36 hours, preferably about 12 to 24 hours.
The compound having general formula [III] that is obtained through the present reaction can be used in the next reaction step either after having been isolated or without being isolated. For carrying out isolation, purification can be carried out through ordinary purification methods such as extraction, concentration, crystallization, and column chromatography.
(b) Manufacture of Compound [I] from Compound [III]
The present is a step of deprotecting the macrocyclic compound having general formula [III] by removing the thiol protecting group (R2) thereof, and forming a thiazoline ring through an intramolecular cyclization reaction between the produced thiol group and an amide group.
Using the macrocyclic compound having general formula [III] obtained in (a), reaction is carried out under strongly acidic conditions in a suitable solvent, whereby deprotection through removal of the thiol protecting group (R2) and the intramolecular cyclization reaction proceed simultaneously, and hence substance GM-95 having general formula [I] is produced. The solvent may be any solvent so long as it is one that does not get involved in the reaction; examples are chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, dimethylformamide, and so on, with dichloromethane being preferable. Such solvents may be used alone, or a mixture thereof may be used. Examples of the acid used in setting the strongly acidic conditions are titanium tetrachloride, trifluoroacetic acid/anisole, hydrofluoric acid/anisole, hydrogen chloride/acetic acid, HF, and so on, with titanium tetrachloride being preferable. The amount used of the acid is 1 to 100 mol, preferably 30 to 60 mol, per mol of the compound having general formula [III]. The reaction temperature is about 0 to 100xc2x0 C., preferably 20xc2x0 C. to 40xc2x0 C. The reaction time is 1 to 5 days, preferably 2 to 4 days.
The substance GM-95 having general formula [I] that is obtained through the present reaction can be purified through ordinary purification methods such as extraction, concentration, crystallization, and column chromatography.
Steps of Manufacturing Compound [II] from Compound [IV-a] and Compound [V-a]
(a) Manufacture of Compound [VI] from Compound [IV-a] and Compound [V-a]
The present is a step of carrying out dehydration condensation between an acetal derivative having general formula [IV-a] and a thiol derivative having general formula [V-a] in a suitable solvent.
The solvent used in this intermolecular dehydration condensation reaction may be any solvent so long as it is inert to the reaction; examples are chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide, and so on, with dimethylformamide being preferable. Such solvents may be used alone, or a mixture thereof may be used. Examples of the dehydration condensing agent used are dicyclohexylcarbodiimide, a water-soluble carbodiimide, diethylphosphorocyanidate, diphenylphosphoryl azide, triphenylphosphine/diethyl azodicarboxylate, and so on, with a water-soluble carbodiimide being preferable. As a water-soluble carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is preferable. In the reaction, the compound having general formula [V-a] can be used in an amount of 0.8 to 1.2 mol, and the dehydration condensing agent in an amount of 1 to 2 mol, preferably 1.0 to 1.3 mol, per mol of the compound having general formula [IV-a]. Furthermore, to promote the reaction and inhibit side reactions, it is preferable to add 1-hydroxybenzotriazole monohydrate, with the proportion used thereof being about 1 to 1.5 mol per mol of the compound having general formula [IV-a]. The reaction temperature is about 0 to 100xc2x0 C., preferably about 10xc2x0 C. to 30xc2x0 C. The reaction time is about 6 to 30 hours, preferably about 8 to 24 hours.
The compound having general formula [VI] that is obtained through the present reaction can be used in the next reaction step either after having been isolated or without being isolated. In the case of carrying out isolation, purification can be carried out through ordinary purification means such as extraction, concentration, crystallization, and column chromatography.
(b) Manufacture of Compound [II] from Compound [VI]
The present is a step of deprotecting the amide derivative having general formula [VI] by removing the carboxyl protecting group and the amino protecting group (R3 and R4), and then carrying out intramolecular cyclization between the amino group and the carboxyl group through intramolecular dehydration condensation.
i) In the above reaction, the deprotection of the amide derivative having general formula [VI] through removal of the carboxyl protecting group (R3) and the amino protecting group (R4) is carried out as follows.
Removing the amino protecting group (R4) from the amide derivative having general formula [VI] is carried out in the presence of an acid in a suitable solvent. The solvent may be any solvent so long as it is inert to the reaction; examples are dichloromethane, methanol, ethanol, tetrahydrofuran, dimethylformamide, and so on, with dichloromethane and methanol being preferable. Such solvents maybe used alone, or a mixture thereof may be used. Examples of the acid used are mineral acids such as hydrogen chloride and sulfuric acid, and organic acids such as trifluoroacetic acid and formic acid, with hydrogen chloride being preferable.
In the present step, it is preferable to select R4 and the R1""s such that R4 is selectively removed leaving the R1""s intact. A preferable combination of R4 and the R1""s is that R4 is a t-butoxycarbonyl group and the R1""s are methyl groups.
The present step is carried out under anhydrous conditions to prevent removal of the R1""s. The amount of the acid is 1 to 10 mol, preferably 4 to 6 mol, per mol of the substrate. The reaction temperature is about 0 to 80xc2x0 C., preferably about 20 to 50xc2x0 C. The reaction time is about 1 to 24 hours, preferably about 8 to 18 hours.
Removing the carboxyl protecting group (R3) from the amide derivative having general formula [VI] is carried out in the presence of a base in a suitable solvent. The solvent may be any solvent so long as it is inert to the reaction; examples are methanol, ethanol, tetrahydrofuran, dimethylformamide, and so on, with methanol being preferable. Such solvents may be used alone, or a mixture thereof may be used. Examples of the base used are sodium hydroxide, potassium hydroxide, and so on. The amount of the base is 1 to 10 mol, preferably 2 to 6 mol, per mol of the substrate. The reaction temperature is about 0 to 80xc2x0 C., preferably about 20 to 50xc2x0 C. The reaction time is about 1 to 24 hours, preferably about 4 to 18 hours.
It is preferable to select R2 and R3 such that R3 is selectively removed leaving the R2 intact. A preferable combination of R2 and R3 is that R2 is a trityl group and R3 is a methyl group or an ethyl group.
There is no limitation on the order of the acid treatment and base treatment described above, but it is preferable to carry out the acid treatment first and then carry out the base treatment.
ii) After the deprotection described above, the macrocyclic compound having general formula [II] can be obtained through an intramolecular dehydration condensation in a suitable solvent. The solvent may be any solvent so long as it is inert to the reaction; examples are chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, dimethylformamide, and so on, with dimethylformamide being preferable; such solvents may be used alone, or a mixture thereof may be used. Examples of the dehydration condensing agent are dicyclohexylcarbodiimide, a water-soluble carbodiimide, diethyl phosphorocyanidate, diphenylphosphoryl azide, triphenylphosphine/diethyl azodicarboxylate, and so on, with diphenylphosphoryl azide being preferable. At this time, to inhibit intermolecular reaction, it is preferable to carry out the reaction with the concentration of the compound obtained by removing the carboxyl protecting group and the amino protecting group from the compound [VI] at very low concentration. The reaction concentration of the compound obtained from the compound [VI] is 1 to 100 mM, preferably 2 to 20 mM. Moreover, the dehydration condensing agent can be used in an amount of 0.8 to 3 mol, preferably 1 to 2 mol, per mol of the compound obtained from the compound [VI].
To promote the reaction and inhibit side reactions, it is preferable that 1-hydroxybenzotriazole monohydrate, 4-dimethylaminopyridine and triethylamine are present. The proportions used thereof are 1 to 1.5 mol of 1-hydroxybenzotriazole monohydrate, 1 to 1.5 mol of 4-dimethylaminopyridine, and 1 to 2 mol of triethylamine, per mol of the compound obtained by removing the carboxyl protecting group and the amino protecting group from the compound [VI]. The reaction temperature is about 10 to 60xc2x0 C., preferably about 25xc2x0 C. to 35xc2x0 C. The reaction time is about 1 to 6 days, preferably about 2 to 4 days.
The macrocyclic compound having general formula [II] that is obtained through the present reaction can, if necessary, be purified through ordinary purification means such as extraction, concentration, crystallization, and column chromatography.
Steps of Manufacturing Compound [II] from Compound [IV-b] and Compound [V-b]
(a) Manufacture of Compound [VII] from Compound [IV-b] and Compound [V-b]
The present is a step of carrying out dehydration condensation between an acetal derivative having general formula [IV-b] and a thiol derivative having general formula [V-b] in a suitable solvent.
The solvent used in this intermolecular dehydration condensation reaction may be any solvent so long as it is inert to the reaction; examples are chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide, and so on, with dimethylformamide being preferable; such solvents maybe used alone, or a mixture thereof may be used. Examples of the dehydration condensing agent used are dicyclohexylcarbodiimide, a water-soluble carbodiimide, diethyl phosphorocyanidate, diphenylphosphoryl azide, triphenylphosphine/diethyl azodicarboxylate, and soon, with a water-soluble carbodiimide being preferable. As a water-soluble carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is preferable. In the reaction, the compound having general formula [V-b] can be used in an amount of 0.8 to 1.2 mol, and the dehydration condensing agent in an amount of 1 to 2 mol, preferably 1.0 to 1.3 mol, per mol of the compound having general formula [IV-b]. To promote the reaction and inhibit side reactions, it is preferable to add 1-hydroxybenzotriazole monohydrate, with the proportion used thereof being about 1 to 1.5 mol per mol of the compound having general formula [IV-b]. The reaction temperature is about 0 to 100xc2x0 C., preferably about 10xc2x0 C. to 30xc2x0 C. The reaction time is about 4 to 30 hours, preferably about 8 to 24 hours.
The compound having general formula [VII] that is obtained through the present reaction can be used in the next reaction step either after having been isolated or without being isolated. In the case of carrying out isolation, purification can be carried out through ordinary purification means such as extraction, concentration, crystallization, and column chromatography.
(b) Manufacture of Compound [II] from Compound [VII]
The present is a step of deprotecting the amide derivative having general formula [VII] by removing the amino protecting group and the carboxyl protecting group (R5 and R6), and then carrying out intramolecular cyclization between the amino group and the carboxyl group through intramolecular dehydration condensation.
i) In the above reaction, deprotecting the amide derivative represented by general formula [VII] through removal of the carboxyl protecting group and the amino protecting group (R6 and R5) can be carried out in the same way as the deprotection of the amide derivative having general formula [VI] through removal of the carboxyl protecting group (R3) and the amino protecting group (R4).
Specifically, removing the amino protecting group (R5) from the amide derivative having general formula [VII] is carried out in the presence of an acid in a suitable solvent. The solvent may be any solvent so long as it is inert to the reaction; examples are dichloromethane, methanol, ethanol, tetrahydrofuran, dimethylformamide, and so on, with dichloromethane and methanol being preferable. Such solvents may be used alone, or a mixture thereof may be used. Examples of the acid are mineral acids such as hydrogen chloride and sulfuric acid, and organic acids such as trifluoroacetic acid and formic acid, with hydrogen chloride being preferable.
In the present step, it is preferable to select R15 and the R1""s such that R5 is selectively removed leaving the R1""s intact. A preferable combination of R5 and the R1""s is that R5 is a t-butoxycarbonyl group and the R1""s are methyl groups.
The present step is carried out under anhydrous conditions to prevent removal of the R1""s. The amount of the acid is 1 to 10 mol, preferably 4 to 6 mol, per mol of the substrate. The reaction temperature is about 0 to 80xc2x0 C., preferably about 20 to 50xc2x0 C. The reaction time is about 1 to 24 hours, preferably about 8 to 18 hours.
Removing the carboxyl protecting group (R6) from the amide derivative having general formula [VII] is carried out in the presence of a base in a suitable solvent. The solvent may be any solvent so long as it does not get involved in the reaction; examples are methanol, ethanol, tetrahydrofuran, dimethylformamide, and so on, with methanol being preferable. Such solvents may be used alone, or a mixture thereof may be used. Examples of the base used are sodium hydroxide, potassium hydroxide, and soon. The amount used of the base is 1 to 10 mol, preferably 2 to 6 mol, per mol of the substrate. The reaction temperature is about 0 to 80xc2x0 C., preferably about 20 to 50xc2x0 C. The reaction time is about 1 to 24 hours, preferably about 4 to 20 hours.
In the present step, it is preferable to select R2 and R6 such that R6 is selectively removed leaving R2 intact. A preferable combination of R2 and R6 is that R2 is a trityl group and R6 is a methyl group or an ethyl group.
There is no limitation on the order of the acid treatment and base treatment described above, but it is preferable to carry out the acid treatment first and then carry out the base treatment.
ii) After the deprotection described above, the macrocyclic compound having general formula [II] can be obtained through an intramolecular dehydration condensation reaction in a suitable solvent. For this intramolecular dehydration condensation reaction, the method described earlier (in the manufacture of [II] from [VI]) can be used.
Specifically, the solvent may be any solvent so long as it is inert to the reaction; examples are chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, dimethylformamide, and so on, with dimethylformamide being preferable; such solvents maybe used alone, or a mixture thereof may be used. Examples of the dehydration condensing agent are dicyclohexylcarbodiimide, a water-soluble carbodiimide, diethyl phosphorocyanidate, diphenylphosphoryl azide, triphenylphosphine/diethylazodicarboxylate, and so on, with diphenylphosphoryl azide being preferable. At this time, to inhibit intermolecular reaction, it is preferable to carry out the reaction with the concentration of the compound obtained by removing the carboxyl protecting group and the amino protecting group from the compound [VII] at very low concentration. The reaction concentration of the compound obtained by removing the carboxyl protecting group and the amino protecting group from the compound [VII] is 1 to 100 mM, preferably 2 to 20 mM. Moreover, the dehydration condensing agent can be used in an amount of 0.8 to 3 mol, preferably 1 to 2 mol, per mol of the compound obtained by removing the carboxyl protecting group and the amino protecting group from the compound [VII].
To promote the reaction and inhibit side reactions, it is preferable that 1-hydroxybenzotriazole monohydrate, 4-dimethylaminopyridine and triethylamine are present. The proportions used thereof are 1 to 1.5 mol of 1-hydroxybenzotriazole monohydrate, 1 to 1.5 mol of 4-dimethylaminopyridine, and 1 to 2 mol of triethylamine, per mol of the compound obtained by removing the carboxyl protecting group and the amino protecting group from the compound [VII].
The reaction temperature is about 10 to 60xc2x0 C., preferably about 25xc2x0 C. to 35xc2x0 C. The reaction time is about 1 to 6 days, preferably about 2 to 4 days.
The macrocyclic compound having general formula [II] that is obtained through the present reaction can, if necessary, be purified through ordinary purification means such as extraction, concentration, crystallization, and column chromatography.
Each of the trisoxazole derivatives having general formulae [IV-a], [IV-b], [V-a] and [V-b], which are raw materials, is either a publicly known compound, or else can be synthesized in accordance with methods disclosed in documents such as J. Org. Chem., 58, 1575(1993), J. Org. Chem., 58, 3604 (1993), Tetrahedron Lett., 33, 6267 (1992), Tetrahedron Lett., 35, 2477 (1994), Tetrahedron, 51, 7321 (1995) J. Am. Chem. Soc., 115, 8449 (1993), Tetrahedron Lett., 27, 163(1986), J. Org. Chem., 43, 1624(1978), and Tetrahedron Lett., 38, 331 (1997).
Furthermore, in the present invention, due to asymmetric carbons in the compounds used as the raw materials, optical isomers or diastereomers may exist and in each reaction step; any of these, or a mixture thereof, can be used in the reaction steps in the present invention.
For example, if the configuration of the asymmetric carbon indicated by xe2x80x98*xe2x80x99 in compound [V-a] or [V-b] in the scheme of the present invention is R, then the configuration of the asymmetric carbon indicated by xe2x80x98*xe2x80x99 in the thiazoline ring in compound [I] will also be R; in turn if the configuration of the asymmetric carbon indicated by xe2x80x98*xe2x80x99 in compound [V-a] or [V-b] is S, then the configuration of the asymmetric carbon indicated by xe2x80x98*xe2x80x99 in the thiazoline ring in compound [I] will also be S. Moreover, if the configuration of the asymmetric carbon indicated by xe2x80x98*xe2x80x99 in compound [V-a] or [V-b] is RS, then the configuration of the asymmetric carbon indicated by xe2x80x98*xe2x80x99 in the thiazoline ring in compound [I] will also be RS, and if necessary optical resolution can be carried out.